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Application of DNA methylation analysis to tretment of gastrointestinal cancer.

Research Project

Project/Area Number 14370188
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionSapporo Medical University

Principal Investigator

YOSHIDA Yukinari  Sapporo Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (60311411)

Co-Investigator(Kenkyū-buntansha) ITOH Fumio  Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (90223180)
YAMAMOTO Hiroyuki  Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (40332910)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 2003: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2002: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordsDNA methylation / CIMP / gastrointestinal cancer / methylation inhibitor / histone acetylation / anti-cancer drug sensitivity / taxane / CHFR / 消火器癌 / ヒストン脱アセチル化 / CpGアイランド / CHFR遺伝子 / チェックポイント
Research Abstract

CpG island methylator phenotype(CIMP) has been found to be implicated in the development of various malignancies. We have previously reporeted that a subset of gastric and colorectal cancers domonstrated CIMP. CIMP positive gastrointestinal tumors present a potentially distinct genetic pathway in which p53 or K-ras mutations are rare. In the other hand, hypermethylation of p16 or MLH1 gene promotor, leading to gene silencing, have been frequently shown.
In the present study, we examined the methylation status of CHFR, which delays chromosome condensation during prophase in response to mitotic stress caused by microtubule poisoning, in gastrointestinal cancers. CHFR expression was silenced by DNA methylation of the gene promotor in 40% of both primary gastric and colorectal cancers. In addition, histones H3 and H4 were found to be deacetylated in cell lines showing aberrant methylation, indicating a role for histone deacetylation in the methylation-dependent gene silencing. Furthermore, the absence of CHFR is associated with sensitivity of cells to mitotic stress caused by taxanes, microtubule inhibitors, and restoration of CHFR expression by 5-aza-2'-deoxycytidine restored the checkpoint. By affecting mitotic checkpopint function, CHFR inactivation likely plays a role in tumorigenesis in gastrointestinal cancers. Moreover, the abberant methylation of CHFR appears to be a good molecular marker with which to predict the sensitivity of gastrointestinal cancers to microtubule inhibitors.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Satoh A, Yoshida Y et al.: "Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer."Cancer Res.. 63. 8606-8613 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toyota M, Yoshida Y et al.: "Epigenetic inactivation of CHFR in human tumors."Proc.Natl.Acad.Sci. USA. 100(13). 7818-7823 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Satoh A, Yoshida Y et al.: "Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer."Cancer Res.. 63. 8608-8613 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toyota M, Yoshida Y et al.: "Epigenetic inactivation of CHFR in human tumors."Proc.Natl.Acad.Sci.USA. 100(13). 7818-7823 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Satoh A, Yoshida Y et al.: "Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer."Cancer Res.. 63. 8606-8613 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toyota M, Yoshida Y et al.: "Epigenetic inactivation of CHFR in human tumors."Proc.Natl.Acad.Sci.USA. 100(13). 7818-1823 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takekawa M, Yoshida Y. et al.: "Smad-dependent GADD45β expression mediates delayed activation of p38 MAF kinase by TGF-β"EMBO J. 23. 6743-6782 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Toyota M, Yoshida Y. et al.: "Epigenetic inactivation of CHFR in human tumors"Proc. Nati. Acad. Sci. USA.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohno S, Yoshida Y et al.: "The antisene approach in AL amyloidosis : Detection of monoclonal immunoglobulin and inhibition of its production by antisense oligonucleotides in in vitro and in vivo models"J Immunol. 169. 4039-4045 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kikuchi T, Yoshida Y et al.: "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors"Oncogene. 21. 2741-2749 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto H, Yoshida Y. et al.: "Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability"Genes Chromosomes Cancer. 33. 322-325 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sasaki Y, Yoshida Y. et al.: "Increased expression of t-fimbrin gene after DNA damage in cho cells and inactivation of t-fimbrin by CpG methylation in human colorectal cancer cells"Int J Cancer. 97. 211-216 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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